1. Field of Invention
The current invention concerns a method for protection of heart or heart tissue by limiting metabolic and ionic abnormalities developed during, following or associated with ischemia and resulting in damage of the heart or heart tissue. In particular, the current invention concerns the method for protecting the heart from ischemic damage caused by metabolic or ionic abnormalities by administering to a subject in need thereof either a therapeutically effective amount of a compound which reduces NADH/NAD.sup.+ ratio and stimulates glycolysis to produce ATP or a therapeutically effective amount of a compound which inhibits the cotransporter of sodium-potassium-chloride. The method is either therapeutic, whereby in order to limit ischemic damage to the heart and to the heart tissue, the compound is administered to the subject immediately or as soon as possible after the ischemic event, or prophylactic, whereby the compound is administered to the subject who is at risk of developing the ischemia prior to the ischemic insult.
2. Background Art and Related Art Disclosures
Cardiovascular disease presents a major cause of morbidity and mortality. This is particularly true for diabetic patients whose incidence of heart failure after myocardial infarction is significantly greater than for non-diabetic patients. Diabetic patients are also at increased risk for diabetic cardiomyopathy independent of coronary disease.
Previous investigations of diabetic heart vis-a-vis its vulnerability to an ischemic insult led to controversial findings. Some studies (Circ. Res., 62:931 (1988) and J. Mol. Cell. Cardiol., 24:411 (1992)) indicated that diabetes protects the heart from ischemia and reperfusion injury. The other studies indicated that diabetic hearts are less likely to survive an ischemic result (Circ. Res., 44:322 (1979) and 62:975 (1988)). While the vulnerability of the diabetic myocardium was studied using variables such as insulin treatments or insulin and non-insulin dependency, these studies primarily concentrated on determination and measurement of the infarct size and on impairment of contractile function but not on any cellular or intracellular changes.
This was unfortunate, as there seem to be some abnormalities present in the diabetic patients at the myocyte level which increase risk of these patients during ischemia. One of these found abnormalities is alteration in ion transport and ion regulation in myocytes. These abnormalities include elevated intracellular calcium and sodium and reduced ATPase activity. Additionally, the sodium-calcium exchanger was found to be severely impaired in diabetic hearts (Mol. Cell Biochem., 107:1-20 (1991)).
However, up to date, the ionic changes occurring as a response to ischemic insult in normally functioning heart or under the normal perfusion conditions, during global zero-flow ischemia, low-flow ischemia and reperfusion were not studied and/or correlated to a degree of damage developing as a result of the ischemic insult. Events leading to such metabolic or ionic abnormalities resulting in damage of the heart due to the ischemic insult was never elucidated and the possible treatment or prevention of extent of such ischemic metabolic or ionic abnormalities damage was never described.
Since the ischemic damage determines the mortality and or/survival rate of these patients, it would be highly advantageous to provide a method for preventing and limiting ischemic heart damage and/or for treatment of ischemic damage of the heart tissue.
Aldose reductase inhibitors constitute a class of compounds which have been shown to treat conditions arising from complications such as diabetic neuropathy or nephropathy, to lower lipid levels in blood of mammals, (U.S. Pat. Nos. 4,492,706 and 5,391,551) as well as to treat capillary fragility and modify evolution of diabetic cataracts (U.S. Pat. No. 4,211,772). Certain representative of aldose reductase inhibitors are compounds described in the U.S. Pat. No. 4,939,140. Aldose reductase inhibitors have not been previously connected with limiting or decreasing the extent of the ischemic damage due to metabolic and ionic abnormalities to the heart.
Furosemide and bumetanide were previously used for preservation of heart for transplantation during hypothermic ischemia (J. Mol. Cell Cardiol., 25:1403 (1993). The use of these compounds limiting the extent of metabolic or ionic abnormalities in normal or diabetic hearts was not described.
It is therefore a primary objective of this invention to provide an effective method for treatment and prevention of development of ischemic damage due to metabolic and ionic abnormalities to the heart and heart tissue by providing a compound which can reduce NADH/NAD.sup.+ ratio a stimulate glycolysis to produce ATP or a compound which inhibits cotransport of sodium-potassium-chloride through the myocyte wall.
All patents, publication and other cited references are hereby incorporated by reference in their entirety.